title: Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport.
abstract: The transporter-mediated uptake of drugs from blood into hepatocytes is a prerequisite for intrahepatic drug action or intracellular drug metabolism before excretion. Therefore, uptake transporters, e.g., members of the organic anion transporting polypeptide (OATP) family are important determinants of drug pharmacokinetics. Highly and almost exclusively expressed in hepatocytes are the OATP family members OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3). Drug substrates of OATP1B1 and OATP1B3 include antibiotics and HMG-CoA reductase inhibitors (statins). It has been demonstrated that administration of two or more drugs that are substrates for these hepatic uptake transporters may lead to transporter-mediated drug-drug interactions, resulting in altered transport kinetics for drug substrates. In this study we investigated whether non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol interact with OATP1B1 and OATP1B3 using the standard substrate BSP and the drug substrate pravastatin. Using human embryonic kidney cells stably expressing OATP1B1 or OATP1B3, we demonstrated that bromosulfophthalein uptake was inhibited by diclofenac, ibuprofen. and lumiracoxib. Of interest, pravastatin uptake was stimulated by these NSAIDs, and for ibuprofen we determined activation constants (EC₅₀ values) of 64.0 and 93.1 μM for OATP1B1- and OATP1B3-mediated uptake, respectively. Furthermore, we investigated whether NSAIDs were also substrates for OATP1B1 and OATP1B3 and demonstrated that only diclofenac was significantly transported by OATP1B3, whereas all other NSAIDs investigated were not substrates for these uptake transporters. These results demonstrated that drugs may interact with transport proteins by allosteric mechanisms without being substrates and, therefore, not only uptake inhibition but also allosteric-induced modulation of transport function may be an important mechanism in transporter-mediated drug-drug interactions.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Kindla
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.forename: Maren
authors.initials: M
authors.lastname: Mieth
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Jörg
authors.initials: J
authors.lastname: König
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D002853:Chromatography, Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000378:metabolism / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism / Q000502:physiology*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013045:Species Specificity; D013379:Substrate Specificity; D013448:Sulfobromophthalein / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013448:Sulfobromophthalein